Osteoarthritis (OA), a non-inflammatory joint disease characterized by degeneration of joint cartilage, can affect one or more parts of the body, including hands and weight-bearing joints such as knees, hips, feet and the spine. When healthy, cartilage allows bones to glide over each other and has a shock absorbing function. In osteoarthritis, the cartilage breaks down and wears away, which eventually allows the bones under the cartilage to rub together, causing the common OA symptoms of pain, swelling, and loss of motion of the joint. Furthermore, in joints such as the knees, osteoarthritis is often accompanied by loss of viscosity of the synovial fluid, a thick, gel-like substance that cushions the joint and provides lubrication to reduce friction of the bones.
Prior to the disease advancement stage of bone-on-bone contact, a significant hallmark of OA is the loss of glycosaminoglycan (GAG), a polysaccharide that contains many negative charges and thus causes many water molecules to be withheld and immobilized within the cartilage tissue. The water molecules play a significant role in the mechanical properties of cartilage, imparting the ability of the tissue to bear compressive loads. This is an effect of the tissue being biphasic, i.e. being composed of a solid component and a fluid component; during loading of healthy cartilage, the load is initially borne mostly by the fluid component, which has ramifications both in compression properties and consequently for lubrication, as the load being borne mainly by the fluid component of the tissue allows less load to be borne by the solid components, thereby minimizing the frictional force on the solid components.
As GAG depletes during the progression of OA, the tissue withholds water molecules less effectively. Hydraulic permeability increases, allowing water to flow out of the tissue under loading faster than it would if the tissue were not osteoarthritic. As a result, compressive moduli and tau values (time to stress equilibration under strain-controlled loading or time to strain equilibration under stress-controlled loading) of osteoarthritic cartilage are typically lower than those of healthy cartilage, and coefficient of friction of osteoarthritic cartilage is typically greater than that of healthy cartilage. In addition, osteoarthritic cartilage typically exhibits regions with significant variability in compressive strength. From a mechanics standpoint, adjacent regions of a single tissue having disparate compressive strength often exacerbates tissue deterioration under loading compared to a tissue with homogeneous compressive strength throughout the tissue's entirety.
Osteoarthritis is mainly associated with aging, with a prevalence of approximately 80% in individuals over 65. Despite being a condition that causes most problems to populations after retirement age, osteoarthritis is also rated the highest cause of work loss in the U.S. and Europe. In addition to age, risk factors known to be associated with osteoarthritis include obesity, traumatic injury and overuse due to sports and occupational stresses.
There is currently no cure for osteoarthritis, and available arthritis therapies are directed at the symptomatic relief of pain, and at improving, or at least maintaining, joint function. Generally, pain relievers such as non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors are used, along with physical therapy. However, in the context of the recent withdrawals of COX-2 inhibitors, physicians are even more limited in their choice of treatment for osteoarthritis.
Viscosupplementation, a procedure involving the injection of gel-like substances (generally hyaluronates, also known as hyaluronic acids) into the joint to supplement the viscous properties of synovial fluid, has been shown to relieve pain in many osteoarthritis patients who do not get relief from analgesic drugs. The technique has been used in Europe and Asia for several decades, but the U.S. Food and Drug Administration did not approve it until 1997. In current procedures of viscosupplementation, hyaluronate preparations are injected to replace or supplement the body's natural hyaluronan, a polysaccharide component of synovial fluid. The injections coat the articular cartilage surface, and thus provide a possible prophylactic barrier for the articular cartilage in addition to increasing the viscosity of the synovial fluid. However, due to their short lifetime within the joint (about a couple of days), hyaluronate preparations currently available have only limited long-term benefit to the patient and require injection of large quantities of the preparation and/or repeated injections.
In an effort to combat the loss of GAGS during OA, GAGS may be taken orally as supplements (chondroitin sulfate, glucosamine, and other saccharide-based supplements), and are also applied as topical creams. However, these molecules do not enter the bulk of the cartilage and remain there for long durations, and their direct effect of integrating within the tissue is transient. An alternate hypothesis purports that the GAGS are not directly incorporated into the solid matrix of the tissue but rather are used as building blocks by chondrocytes to produce new GAG through natural synthesis. While this hypothesis stands to be further tested, it should be noted that chondrocyte production of GAG is downregulated during OA, and introducing excess supplementary GAG does not necessarily equate with increased incorporation of GAG into the cartilage extracellular matrix.
Accordingly, there is a strong need in the art for compositions and methods to treat, repair or supplement tissues.